Human testis-expressed (TEX) genes: areview focused on spermatogenesis andmale fertilityHela Bellil1, Farah Ghieh2,3, Emeline Hermel2,3, Béatrice Mandon-Pepin2,3 and François Vialard1,2,3*
Abstract
Spermatogenesis is a complex process regulated by a multitude of genes. The identification and characterization ofmale-germ-cell-specific genes is crucial to understanding the mechanisms through which the cells develop. Theterm “TEX gene” was coined by Wang et al. (Nat Genet. 2001; 27: 422–6) after they used cDNA suppressionsubtractive hybridization (SSH) to identify new transcripts that were present only in purified mouse spermatogonia.TEX (Testis expressed) orthologues have been found in other vertebrates (mammals, birds, and reptiles), invertebrates,and yeasts. To date, 69 TEX genes have been described in different species and different tissues. To evaluate theexpression of each TEX/tex gene, we compiled data from 7 different RNA-Seq mRNA databases in humans, and 4 inthe mouse according to the expression atlas database.Various studies have highlighted a role for many of these genes in spermatogenesis. Here, we review currentknowledge on the TEX genes and their roles in spermatogenesis and fertilization in humans and, comparatively, inother species (notably the mouse). As expected, TEX genes appear to have a major role in reproduction in generaland in spermatogenesis in humans but also in all mammals such as the mouse. Most of them are expressedspecifically or predominantly in the testis. As most of the TEX genes are highly conserved in mammals, defects inthe male (gene mutations in humans and gene-null mice) lead to infertility. In the future, cumulative data on thehuman TEX genes’ physiological functions and pathophysiological dysfunctions should become available and islikely to confirm the essential role of this family in the reproductive process. Thirteen TEX genes are now referencedin the OMIM database, and 3 have been linked to a specific phenotype. TEX11 (on Xq13.1) is currently the genemost frequently reported as being associated with azoospermia.
* Correspondence: [email protected]épartement de Génétique, CHI de Poissy St Germain en Laye, Poissy,France2Université Paris-Saclay, UVSQ, INRAE, BREED, F-78350 Jouy-en-Josas, FranceFull list of author information is available at the end of the article
Bellil et al. Basic and Clinical Andrology (2021) 31:9 https://doi.org/10.1186/s12610-021-00127-7
La spermatogenèse est un processus complexe régulé par une multitude de gènes. L’identification et lacaractérisation des gènes spécifiques des cellules germinales mâles sont essentielles pour comprendre lesmécanismes par lesquels les cellules se développent. Le terme «gène TEX» a été inventé par Wang et al. (Nat Genet.2001; 27: 422–6) après avoir utilisé l’hybridation soustractive d’ADNc (SSH) pour identifier de nouveaux transcrits quin’étaient présents que dans la spermatogonie de souris. Puis, des orthologues TEX ont été trouvés chez d’autresvertébrés (mammifères, oiseaux et reptiles), des invertébrés et des levures. À ce jour, 69 gènes TEX (Testis expressed)ont été décrits dans différentes espèces et différents tissus. Pour évaluer l’expression de chaque gène TEX/tex, nousavons compilé les données de 7 bases de données différentes d’ARNm RNA-Seq chez l’homme, et 4 chez la sourisselon la base de données de l’atlas d’expression.Diverses études ont mis en évidence le rôle de plusieurs de ces gènes dans la spermatogenèse. Ici, nous passonsen revue les connaissances actuelles sur les gènes TEX et leurs rôles dans la spermatogenèse et la fécondation chezl’humain et, comparativement, chez d’autres espèces (notamment la souris). Comme prévu, les gènes TEX semblentavoir un rôle majeur dans la reproduction en général et dans la spermatogenèse chez l’homme, mais aussi chezd’autres mammifères comme la souris. La plupart d’entre eux sont exprimés spécifiquement ou principalementdans les testicules. Comme la plupart des gènes TEX sont hautement conservés chez les mammifères, des défautschez le mâle (mutations géniques chez l’homme et KO murin) conduisent à l’infertilité. À l’avenir, l’accumulation desdonnées sur les fonctions physiologiques et les dysfonctionnements physiopathologiques des gènes TEX humainsdevraient devenir disponibles et confirmer le rôle essentiel de cette famille dans le processus de reproduction.Treize gènes TEX sont désormais référencés dans la base de données OMIM, et 3 ont été liés à un phénotypespécifique. TEX11 (sur Xq13.1) est. actuellement le gène le plus fréquemment rapporté comme étant associé àl’azoospermie.
IntroductionMale and/or female infertility (defined as the inability toconceive a child within 1 year of regular unprotectedintercourse) affects up to 15% of couples [1]. Infertility isdue to male factors in 40–50% of couples and can bedue to environmental exposure, infections, immuneproblems or hormone deficiencies [2]. In 15–30% of allcases, genetics factors are involved [3].Male germ cell development (spermatogenesis) is a
tightly regulated developmental process that occursthrough successive mitotic, meiotic and post-meioticphases (in spermatogonia, spermatocytes and sperma-tids, respectively) [4]. During spermatogenesis, geneexpression is regulated in three ways: intrinsically, inter-actively and extrinsically. The intrinsic program deter-mines which genes are used and when these genes areexpressed. The interactive regulation involves communi-cation between germ cells and somatic cells. Lastly, theextrinsic program influences the interactive processthrough hormonal regulation [5].The regulation of spermatogenesis involves the expres-
sion of a large number of genes in a precise cell- andstage-specific program [5]. A comprehensive under-standing of spermatogenesis requires the identificationand functional characterization of the 2300 or so genesthat are predominantly expressed in the testes [6]. In the2000s, the use of cDNA (complementary DNA) library
construction techniques and the comparison of genetranscription profiles under different physiological con-ditions enabled the identified of genes specificallyexpressed in testis or gonads (named as the testis-expressed (Tex) genes). However, no information on thenew gene family’s function (notably in the testis) was ini-tially available [7].Here, we review current knowledge on the TEX genes
in humans and other species (notably the mouse) andfocus on the genes’ roles in spermatogenesis andfertilization. Importantly, some of the TEX genes consti-tute promising biomarkers of male infertility.
How the first TEX genes were identified andnamedThe term “TEX” for testis-expressed was coined by Wanget al. after they used cDNA suppression subtractivehybridization (SSH) to identify new transcripts that werepresent only in purified mouse spermatogonia [7]. Ten ofthe 23-novel germ-cell-specific genes, highly or exclusivelytestis-expressed (Tex11 to 20) had not been annotatedpreviously, and the human TEX orthologs were subse-quently described [7]. Most of these genes have since beenfound to have a function in spermatogenesis, and add-itional TEX genes have been identified.Before Wang et al.’s report, the Tex genes had been
confused with the t-complex testis-expressed (Tctex)
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genes. The mouse t-complex corresponds to a portion ofmouse chromosome 17 that had been identified inmouse t-haplotypes [8]. This t-haplotype contains fournon-overlapping, paracentric inversions that span a gen-etic distance of 20 cM (centiMorgan). This results in a100–200-fold suppression of recombination, which inturn keeps the haplotypes intact and leads to their diver-gence from the wild-type chromosomes. There are rela-tively few Tctex genes: Tctex3, Tctex7, Tctex8, Tctex9,Tctex10, Tctex11, and Tctex12. The genes are expressedpredominantly in the germ cells of the testis, and map tovarious regions of the t-complex. Three genes are moreabundantly expressed at the pachytene stage; threeothers are expressed after meiosis, and one (Tctex10) isexpressed at all stages of spermatogenesis [8]. Twoorthologs have been observed in the human: TCTEX6(also named TEX6) and PPP1R11 (TCTEX5). To date, 69TEX or Tex genes have been described in humans ormouse models. However, as described below, these genesdo not constitute a homogeneous family; in contrast asthe HOX (homeobox) or PAX (paired box) or RHOX(X-linked reproductive homeobox) genes with high se-quence identity and very similar functions, the sole com-mon feature of the Tex/TEX genes is their expression(solely or primarily) in the testis. After Wang et al.’s re-port, new testis-specific genes have been included in theTEX family and numbered sequentially. The TCTEXand TEX gene families are not related as such.
The TEX gene familyAs mentioned above, 69 expressed TEX or Tex genes(61 human genes and 61 mouse genes (Fig. 1)) arelisted in the main databases (https://gtexportal.org/home/, https://www.ensembl.org/index.html, https://www.omim.org/, etc.). These genes are distributedthroughout the genome. To evaluate the expression ofeach TEX/Tex gene, we compiled data from 7 differ-ent RNA-Seq mRNA databases in humans, and 4 in
the mouse according to the expression atlas database(https://www.ebi.ac.uk/gxa/home).The 7 databases for RNA-Seq mRNA results in
humans were:
(1) the Genotype-Tissue Expression database (http://www.genome.ucsc.edu/gtex.html): 53 tissue.
(2) Hallstrom et al.’s database [9]: 95 individualsrepresenting 27 tissues.
(3) the Uhlen laboratory’s database (https://www.proteinatlas.org/humanproteome): 122 individualsrepresenting 32 tissues.
(4) the Illumina Body Map [10]: 16 tissues.(5) the ENCODE project database from Snyder’s lab
(https://www.encodeproject.org/): 13 tissues.(6) the mammalian database from Kaessmann’s lab
[11]: 6 tissues, used to investigate the evolution ofgene expression levels in different organs.
(7) the Functional Annotation of the MammalianGenome (FANTOM) 5 project (https://fantom.gsc.riken.jp/data/): 57 tissues
The 4 databases for RNA-Seq mRNA results in themouse were:
(1) the mammalian database from Kaessmann’s lab[11]: 6 tissues (as in humans).
(2) the FANTOM database 5 projects: (https://fantom.gsc.riken.jp/data/): 35 tissues
(3) the strand-specific RNA-seq of nine C57BL6 mousetissues: 8 tissues.
(4) Soumillon et al.’s database on brain, liver, and thewhole testis [12]: 3 tissues
The data are reported in Table 1 (for humans), Table 2(for mice), and Table 3 (for other species). For eachgene, the highest level of tissue mRNA expression andthe mean testis ratio (the ratio between testis expression
Fig. 1 TEX expression according to species. TEX genes are common to the different species mentioned above, others are specific to each specie.Blue circle included TEX genes expressed in human, green circle included Tex genes expressed in mouse, red circle included tex genes expressedin mouse, red circle included tex genes expressed in other mammals, brown circle included tex genes expressed in birds, yellow circle includedtex genes expressed in reptile
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and the total expression level for all other tissues) werereported in humans and mice. Protein expression evalu-ated according to the Human Protein Atlas (https://www.proteinatlas.org/) and the Human Proteome Map[13] was only reported for humans. The site of expres-sion in the human testis was reported according to theHuman Protein Atlas.tex orthologues have been found in other vertebrates
(mammals (mainly Rattus norvegicus, Macaca mulatta,Equus caballus and Bos taurus), birds (Gallus gallus),and reptiles), invertebrates (Drosophila melanogaster andCaenorhabditis elegans), and yeasts (Saccharomyces cere-visiae) (Table 3). RNA expression in species other thanthe human was reported according to the ExpressionAtlas (https://www.ebi.ac.uk/gxa/home).In the following paragraphs, TEX1 to TEX10 genes
are not considered. As mentioned above, TCTEXgenes are not considered to be members of the TEXfamily, even though mutations in some of them (suchas TEX8 and CAPZA3) result in male infertility in themouse (due to sperm with abnormally shaped headsand poor motility). Ultimately, only 62 TEX geneshave been defined as such.
Evolutionary conservation of the TEX genesData are summarized in Fig. 1
Conservation of identity between vertebrates andinvertebratesFifty-three of the 62 genes reported in Tables 1, 2, 3 donot have identified or reported orthologues in inverte-brates. For the 9 other genes (all of which are testis-specific in humans), orthologues have been identified inDrosophila melanogaster, Caenorhabditis elegans and/orSaccharomyces cerevisiae. Five of the 9 genes (TEX13A,B, C, D and TEX28) are also testis-specific in othermammals – indicating a high degree of conservation anda strong probable impact on spermatogenesis. TEX13 isthought to be the ancestral gene. However, a large pro-portion of the TEX genes appear to be vertebrate-specific - confirming the differences in spermatogenesisbetween vertebrates and invertebrates [14].
Conservation of identity between vertebratesThirty-nine of the 62 genes reported in Tables 1, 2, 3are expressed in humans, mice, and other mammals.Twenty are also expressed in birds and reptiles, 1 is only
Table 1 Human mRNA TEX gene expression, TEX expression and localization, OMIM reference
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expressed in a bird, 1 is only expressed in a reptile, and17 are not expressed in birds or reptiles (and so areprobably mammal-specific). Thirty-three of the 39 genesare expressed specifically in the testis (in 10 cases) orpredominantly in the testis (in 22 cases). For theremaining 6 genes, the highest level of gene expressionis not observed in the testis. Four of these 6 genes arenot even testis-specific (Table 1).Of the 62 genes reported in Tables 1, 2, 3, 6 are solely
expressed in human. Three are pseudogenes (TEX21P,28P1 and 28P2), 2 considered to code for antisenseRNAs (TEX26-AS1 and TEX36-AS1), and the sixth isTEX41. The RNA expression data (when available) sug-gests that these 6 genes are testis-specific or at leastmuch more strongly expressed in the testis than in othertissues. Seven of the 62 genes reported in Tables 1, 2, 3are only expressed in mice; 3 of these are testis-specificexpression or a very high testis expression level. For thelast 10 genes, RNA expression has been identified inother vertebrates (but not in humans or mice) and ap-pears to be generally testis-specific (mean testis ratios:from 0.944 to 1).
Conservation of identity between humans and miceWhen comparing humans and mice, the degree of nu-cleotide identity sequence ranges from 8.00% (forTEX39C) to 94.07% (for TEX30). However, when consid-ering only those genes (n = 26) with a mean testis RNA
ratio below 0.5 in humans and mice, the degree of nu-cleotide sequence identity ranges from 31.0% (forTEX29) to 86.45% (for TEX12). The 8 genes that aretestis-specific in humans are also testis-specific in themouse. Given the high observed degree of identity, stud-ies of TEX gene function in the mouse are likely to berelevant.
Tex gene expression and function in the mouseTex gene was first reported by Wang et al. in 2001 [7].Ten of the 25 testis expressed genes, 10 (Tex11 to 20)had not been described previously, and 3 (Tex15, 19 and20). were expressed in the ovary. A human ortholog hasbeen identified in 5 cases (Tex11 to 15). The analysis oftestis cDNA libraries has since enabled the discovery ofmany other similar genes. Of the 52 Tex genes expressedin the mouse, 13 are testis-specific and 37 have a meantestis ratio below 0.5. For the 8 Tex genes with a meantestis ratio above 0.5, the testis is the tissue with thehighest RNA expression level. The remaining genes havenot been characterized. The available data are summa-rized in Table 4 and detailed in Table 2.One or more mouse models (mainly knock-out
models) have been produced for 47 of the 52 Tex genes.These models have been used to study the Tex genes’function and the resulting level of male fertility. In fact,the male fertility phenotype is not known or has notbeen reported for 25 genes. For Tex20, 23, 169, 189 and
Table 2 Mouse mRNA Tex gene expression, Nucleotids sequence homology (%) and KO models
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Table 3 Others species mRNA tex gene expression and sequence homology
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292, the mouse model is embryo-lethal. For the othergenes, transgenic male mice are fertile in the Tex22, 33,35, 36, 37 and 271 models, subfertile in the Tex 17, 18and 40 models, and infertile in the Tex11, 12, 14, 15, 19,19.1, 38 and 101 models. Below, we provide detailedfunctional information for a small number of these Texgenes.
Tex11The Tex11 gene codes for a protein with a tetratricopep-tide repeat motif (mediating protein-protein interac-tions) and a meiosis-specific domain Spo22 [27, 28]. Thegene has 175 orthologs, and the human vs. mouse se-quence identify is 74%. In the mouse, TEX11 protein isobserved in the cytoplasm and nuclei of type B sperm-atogonia, with the highest level in zygotene spermato-cytes and a basal level in late pachytene spermatocytes[29]. It is the first X-encoded meiosis-specific factor tohave been identified in the mouse. The abundant expres-sion of TEX11 protein in type B spermatogonia andearly spermatocytes suggest that Tex11 has a key role inthe early stages of germ cell development. The gener-ation of Tex11-deficient mice has enabled researchers toelucidate the encoded protein’s role in spermatogenesis.In 2008, Yang et al. generated a Tex11-null mice by de-leting 27 of the gene’s 30 exons. Consequently, sperm-atogenesis was impaired due to chromosomal asynapsisat the pachytene stage and a low level of crossover for-mation at the anaphase I stage. Tex11-deficient sper-matocytes mostly undergo apoptosis at the pachytenestage, while surviving cells display chromosome nondis-junction at the first meiotic division - causes cell deathand male infertility [30]. In another study, Adelmanet al. generated a Tex11 mutant strain by deleting geneexon 3, resulting in a frameshift and a terminationcodon. They found that the mutant males exhibited de-layed repair of double-strand breaks (DSBs) in spermato-cytes. DSB repair and chromosome synapsis are essentialfor genetic integrity; their dysfunction can cause variousdiseases, such as infertility [29]. Tex11 is currently con-sidered to be a constituent of the meiotic nodules in-volved in recombination and that interact with Sycp2 (acomponent of the synaptonemal complex) [30].
Tex12Tex12 is conserved among vertebrates. It encodes a 14.1kDa meiosis-specific protein that does not contain any
known protein domains. Tex12 is specifically located inthe central element structure of the synaptonemal com-plex and is strongly expressed in spermatocytes andspermatids during meiotic cell division exclusively [31,32]. The gene codes for two transcripts (Tex12–201 andTex12–201) and has 116 orthologs. The human andmouse deduced open reading frames code for a 123-residue protein with 86% identity. Tex12-null mice areinfertile. Males show a failure of chromosomal synapsis,whereas females show the loss of ovarian follicles. It hasfurther been demonstrated that Tex12 is a member ofthe synaptonemal complex, which comprises eight pro-teins: SYCP1–3, SYCE1–3, tex12 and SIX6OS1 [33].
Tex13Tex13 is an X-linked gene expressed exclusively in malegerm cells. The Tex13 family has 4 members. Wanget al. identified the first two human orthologs (TEX13Aand B) in 2001 [7]. The degree of human vs. mouse nu-cleotide sequence identity for Tex13 varies from onedatabase to another. Lastly, 4 Tex13 genes have beenidentified: according to Profile Alignment software(https://www.ibi.vu.nl/programs/pralinewww/), the per-centage nucleotide sequence identity is 50% for Tex13A,54% for Tex13B, 30% for Tex13C, and 32% for Tex13D.According to the UniProt database (www.uniprot.org/),the percentage is 23% for TEX13A, 31% for TEX13B, 6%for TEX13C, and 8% for TEX13D. The location ofTEX13 proteins within germ cells is nuclear. Using amouse testicular teratoma cell line (considered to pos-sess the characteristics of male germ cells), Kwon et al.[34] demonstrated that TEX13 expression is regulated ina stage-specific manner at the translational level. Theprotein migrates first to the nuclei of spermatogeniccells and then to the redundant nuclear envelope of thespermatozoon during spermiogenesis. It is found in ma-ture sperm [34]. Remarkably, TEX13 was found to pos-sess transcriptional repressor activity; its overexpressionin GC-2 cells altered the expression levels of 130 genes,suggesting that TEX13 might have a role in transcrip-tional regulation during spermatogenesis [34]. Lastly,Tex13 was the first gene shown to be transcribed inspermatogonia and whose transcripts are then stored ina translationally inactive state until the late meioticstage. Male mice hemizygous for a Tex13a or Tex13b-null allele exhibit normal fertility.
Table 4 Mouse Tex gene expression in the testis
Highest expression in the testis Highestexpression inother tissues
Tex14Tex14 codes for a testis-specific protein. The open read-ing frame’s predicted 1450 amino acid sequence consistsof an ankyrin repeat domain and a protein kinase-C do-main. It shares 64% amino acid sequence identity withthe predicted human TEX14 protein [35]. TEX14 is anessential component of male and female embryonicintercellular bridges. The protein is strongly expressedin the testis and, more specifically, in seminiferous ductcells (Sertoli cells, spermatogonia, spermatocytes, andspermatids) [35]. It is required for both the formation ofintercellular bridges during meiosis and kinetochore-microtubule attachment during mitosis. TEX14 acts bypromoting the conversion of midbodies into intercellularbridges [35]. Tex14-null adult male mice are sterile,while females are fertile [36]. tex14-null males lackedintercellular bridges that connect differentiating germcells, and so spermatogenesis did not progress beyondthe first meiotic division. TEX14 is essential for themaintenance of stable intercellular bridges in gametes ofboth sexes but their loss specifically impairs male mei-osis. Although a low number of oocytes are present inTex14-null neonatal ovaries, females are fertile [36].
Tex15Tex15 codes for a serine-rich protein in the mouse and a3176 amino acid protein in the human (sequenceidentity: 47%) [37]. Tex15 gene is expressed in spermato-gonia and early spermatocytes. Its expression is down-regulated in pachytene spermatocytes and abundant inpostmeiotic germ cells [25]. Tex15-null females are fer-tile, whereas males are sterile with a dramatically re-duced testis size, and a complete lack of pachytenespermatocytes and postmeiotic germ cells [37]. Duringspermatogenesis, Tex15 encodes for a testis-specific pro-tein required for normal chromosome synapsis and mei-otic recombination in germ cells. It is also necessary forDNA DSBs (double-strand breaks) repair. TEX15 mightbe functionally active at different stages in spermatogen-esis. It has been postulated that TEX15 functions down-stream of DSB repair by SPO11 (a subunit of a DNAtopoisomerase VI-like protein complex that is essentialfor meiotic recombination) but upstream of DSB repairby RAD51 (RecombinaseA-like 51) and DMC1 (DNAmeiotic recombinase 1) during the meiotic recombin-ation [37]. It was recently reported that duringspermatogenesis, TEX15 binds to MILI - a member ofthe P-element induced wimpy testis in Drosophila(PIWI) family and that is required for germ celldifferentiation. TEX15 silences transposable elementsthat escape the first round of de novo genome methyla-tion in male germ cells [38]. It has been postulated thatTEX15 is an essential epigenetic regulator that mightoperate as a nuclear effector of MILI by silencing
transposable elements through DNA methylation. It hasalso been reported that in fetal gonocytes, TEX15 inter-acts with MIWI2 (another PIWI family member) and isrequired for piwi-interacting-RNA-directed de novoDNA methylation of transposons [39].
Tex18Tex18 is a small gene identified first in the mouse byWang et al. It has a single 240 bp exon and is specificallyexpressed in male germ cells. The encoded protein doesnot have any identified domains. A human ortholog ofTex18 has not yet been identified [40]. It was later con-firmed that Tex18 is expressed in spermatogonia andthen in other stages of male germ cell development [40].Male Tex18-null mice are subfertile because of abnormalsperm morphology and reduced motility - a phenotypeknown as asthenoteratozoospermia. Spermatid matur-ation is unsynchronized and partially impaired in theseminiferous tubules, suggesting that Tex18 is predom-inantly expressed during spermatid differentiation.
Tex19Tex19 is a mammal-specific duplicate gene (sincerenamed Tex19.1 and Tex19.2) found in the mouse andrat. According to the UniProt database, tex19.1 expres-sion in the embryo decreases after murine embryonicstem and germ cell differentiation. At later stages of de-velopment, Tex19 expression is limited to the germ line.tex19.1 transcripts have also been detected in mousepluripotent stem cells. It is thought that tex19.1 encodesa protein expressed solely in germ cells and pluripotentcells. Male Tex19.1-null mice are infertile, with a defectin meiotic chromosome synapsis, the persistence ofDNA DSBs during meiosis, and a loss of post-meioticgerm cells. It was further demonstrated that TEX19.1[41] and its paralog TEX19.2 [42] interact with PIWIproteins in mouse adult testis to repress transposablegenetic elements and maintain genomic stability throughsuccessive generations. Furthermore, TEX19.1 wasshown to promote Spo11-dependent recombination inmouse spermatocytes [42]. Placental expression ofTex19.1 has also been observed [43]. Accordingly,Tex19.1-null mouse embryos exhibit intra-uterinegrowth retardation and have small placentas. The obser-vation that mobilization of LINE-1 (Long interspersednuclear element 1) retrotransposons is restricted byTEX19.1 in mouse embryonic stem cells [44] may ex-plain the placental dysfunction and small size. Lastly, itwas recently reported that TEX19.1 maintains acetylatedSMC3 (Structural Maintenance of Chromosome 3) andsister chromatid cohesion in postnatal oocytes and pre-vents aneuploidy [45].
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Tex27 (Zfand3: zinc finger an1 domain-containing protein 3)Tex27 is exclusively expressed in adult mouse testis. Itcodes for a protein containing a zinc-finger domain inthe carboxy terminal region and a transactivation do-main in the amino terminal region. TEX27 may be atranscription factor that is preferentially expressed inpostmeiotic cells during mouse spermatogenesis [46]. Inbird and reptile models, it was reported that the genecodes for two different transcripts: a short form mainlyexpressed in the testis, and a long form in the ovary. Se-quence analysis revealed an extra exon in the genomicstructures of the avian and reptilian ZFAND3 genes.TEX27’s physiological functions in the testis and ovaryare thought to differ in terms of germ cell maturationand regulatory mechanisms [47]).
Tex33Tex33 expression is testis-specific; the encoded proteinis found in the cytoplasm of round spermatids but muchless in elongated spermatids [48]. Given that spermato-genesis is normal in male tex33-null mice, Tex33 mightnot be essential [49].
Tex36Tex36 expression is testis-specific but male Tex36-nullmice are fertile with no observable defects in reproduct-ive organs, suggesting that TEX36 is also dispensable tospermatogenesis [50].
Tex37Similarly to Tex36, male Tex37 null mice are fertile andhave no detectable defects (vs. wild-type mice) in thetestis/body weight ratio, epididymal sperm count, andtesticular and epididymal histology [51].
Tex40Tex40 protein (also referred to as CATSPERZ) is locatedin the principal piece of the flagellum. It may represent alate evolutionary adaptation that maximizes fertilizationinside the female mammalian reproductive tract [52].Tex40-null mice are fertile and have a normal spermcount and a normal sperm morphology. However, theflagellum is rigid – impairing motility and leading to re-duced fertility in vivo and in vitro. The human CATSPERZ and murine Catsperz are both auxiliary subunitsof sperm calcium channel pore-forming proteins in-volved in the activation of spermatozoon motility. It wasrecently suggested that downregulation of this protein isthe cause of the low sperm motility observed in astheno-zospermic males [53].
Tex101Tex101 is mainly expressed in testis (from spermato-gonia to spermatids) but it also transcribed during
oogenesis. Mouse TEX101 is a testicular-germ-cell-spe-cific protein predominantly located on the plasma mem-brane of germ cells during gametogenesis. TEX101 isone of the 29 glycosylphosphatidylinositol-anchored pro-teins expressed in the mouse testis, where it might regu-late ion channels through CATSPERZ (cation channel,sperm-associated, auxiliary subunit zeta). When sperm-atogenesis in the testis is complete, the TEX101 proteinremains on the sperm surface - including the tail por-tion. TEX101 is then cleaved from the sperm surfaceand released into the seminal fluid and is no longer de-tectable in male germ cells. The protein interacts withvarious molecules during the post-testicular maturationof spermatozoa, including some members of a disinte-grin and metalloproteinase (ADAM) family [54]. Inhumans, TEX101’s role and interactome have yet to bedetermined.Although Tex101-null mice produce spermatozoa and
oocytes with a normal morphology, males are infertile.Sperm physiology and motility are abnormal, which im-pair sperm migration into the oviduct and hinder the ac-rosome reaction. TEX101 is therefore essential for malefertility; it has been suggested that TEX101 operates as acell surface chaperone involved in the maturation ofproteins required for sperm migration and sperm-oocyteinteraction (such as Adam3) [49–52, 54–57].
Tex261Tex261 is highly expressed in adult testis in general andin the Sertoli cells in particular. It is first expressed after15 days of post-natal life, which coincides with the pres-ence of pachytene cells from the first wave of meiosisduring spermatogenesis. TEX261 expression is not re-stricted to testis (Tables 1 and 2). It is presumably re-lated to (but distinct from) the steroidogenic acuteregulatory gene [58]. More recently, TEX261 was re-ported to modulate the excitotoxic cell death induced byactivation of the N-methyl-D-aspartate receptor - acalcium-permeable ionotropic receptor that has a role inmany neurologic disorders [59]). Tex261-null mice showdefects of the skeleton, immune system, growth/size/body, and adipose tissue (Table 2).
Tex264Although TEX264 expression has been observed in sem-iniferous duct cells and Leydig cells (according to theHuman Protein Atlas), there are no other data on its ex-pression in the testis. In mammalian cells, TEX264 is amajor receptor for selective reticulophagy - a process re-sponsible for the specific sequestration of componentsinside the endoplasmic reticulum alongside the associ-ated ribosomes [60].
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Tex292Tex292 is also referred to as Utp4. At present, the onlydata on TEX292 expression in testis corresponds to a re-port of expression in seminiferous duct cells and Leydigcells. Tex292 inactivation is embryonic-lethal [61]. Theonly available data relates to processes or cell types notassociated to spermatogenesis or germ cells [61].
Human TEX gene expression and defectsmRNA expressionOf the 49 TEX genes expressed in humans, 13 aretestis-specific and 27 show a high expression level intestis, with a mean testis ratio above 0.4 (between0.411 and 0.998). Of the 9 remaining TEX genes, 4are most strongly expressed in the testis for 4, 3 aremore strongly expressed in thyroid or spleen, and 2are pseudogenes. Data are summarized in Table 5and detailed in Table 1.
Protein expressionProtein expression data remains scarce. For 14 TEXgenes, the protein expression pattern is similar to themRNA expression pattern. A testis-specific proteinisoform has been identified for 29 TEX genes, and ex-pression data are missing for 14 other genes. An ovary-specific protein isoform has only been identified forTEX11. A highly variable testicular location has been re-ported for 21 TEX genes (Table 1), although germinalcell expression (from spermatogonia to spermatids) hasbeen reported in 19 cases. Eight proteins are referencedin the OMIM database (https://omim.org/), and defectsin 3 of the coding genes (TEX11, 14 and 15) have beenlinked to phenotypes.
TEX genes, dysregulation of spermatogenesis, and apredisposition to infertilityThirteen TEX genes are now referenced in the OMIMdatabase, and 3 have been linked to a specific phenotype.Here, we report only the data associated with gene de-fects (Tables 6 and 7).
TEX11 (OMIM 300311) [15–20, 62, 63]TEX11 (on Xq13.1) is currently the most frequently re-ported gene as being associated with azoospermia [62].Using an X-chromosome high-resolution microarray,Yatsenko et al. identified the loss of TEX11 exons 9–11
(607del237bp) in two azoospermic patients with homo-geneous or mixed meiotic arrest (47). This in-frame gen-omic deletion predicted a protein lacking 79 amino acidsin the highly conserved sporulation domain SPO22.Additional TEX11 missense and splicing variants werefound in 2.4% of the azoospermic patients but not in anyof the 384 men with normal sperm concentrations [19].Forty variants were subsequently identified by sequen-cing TEX11 exons 2 to 30 and the flanking intronic re-gions in a large cohort of infertile men withnonobstructive azoospermia (n = 246) and in fertile con-trols (n = 175), [20]. Twenty-one of these variants weresingletons (i.e. each was observed in one individual only),while the remaining 19 were observed in 2 or more in-fertile men and/or fertile controls. Eighteen were identi-fied solely in patients with azoospermia. The variantsinclude exonic missense mutations, exonic silent muta-tions, exonic frameshift mutations, and intronic muta-tions. The researchers concluded that TEX11 variantswere detected with a significantly higher frequency inmen with spermatogenic failure than in controls (7.3%versus 1.7%, respectively; p = 0.007) [20]. However, thestudy did not find any differences between pathologicand benign variants. Since then, additional TEX11 mis-sense variants or deletions have been reported [47,4852,53]; suggesting that this X-linked gene has a major roleon azoospermia. Recently, low TEX11 expression was re-ported in a man with Sertoli-cell-only (SCO) syndrome[2]. TEX11 is linked to spermatogenic failure, X-linked,2 syndrome in the OMIM database (OMIM 309120).In 2015, Zhang et al. explored the possible association
between single nucleotide polymorphisms (SNPs) inTEX11 and idiopathic male infertility [63]. The homozy-gous rs6525433 polymorphism genotype was signifi-cantly associated with general infertility (odds ratio(OR) = 1.517, 95% confidence interval (CI):1.070–2.150,p = 0.019) and oligozoospermia (OR = 1.858, 95% CI:1.082–3.192, p = 0.023) - indicating that the rs6525433polymorphism has a role in male infertility. The non-synonymous SNP rs6525433 neutralizes the chargedamino acid at position 130 of the TEX11 protein(K130A), which might have a negative effect on its struc-ture. No association between the TEX11 rs4844247 SNPand male infertility was observed. However, carriers ofboth rs6525433 C and rs4844247 T had an increasedrisk of infertility (95% CI: 1.042–2.542) [63].
Table 5 Human TEX gene expression in the testis
Highest expression in the testis Highestexpressionin othertissues
Mean testis ratio 1 1 to 0.8 0.8 to 0.6 0.6 to 0.4 below 0.4
Bellil et al. Basic and Clinical Andrology (2021) 31:9 Page 11 of 15
TEX12 (OMIM 605791)As in mice, human TEX12 is reportedly essential for thesynaptonemal complex [33]. Even though low TEX12expression has been reported in a patient with SCO syn-drome [2, 32], further studies are required to confirmthe link between TEX12 variants and defectivespermatogenesis.
TEX14 (OMIM 605792) [15, 21–23, 64]As in mice, human TEX14 is essential for forming stableintercellular bridges in germ cells [36]. To date, fewTEX14 genetic variants have been linked to spermato-genesis failure. The first (a 10-bp deletion) variant wasidentified in 2017 in two infertile brothers with nonob-structive azoospermia from a consanguineous IraqiJewish family [23]. The variant leads to a frameshift inthe TEX14 coding region and thus results in an earlystop codon and a truncated protein. Other deleteriousvariants have been associated with infertility, maturationarrest, and SCO phenotypes [22, 64]. Taken as a whole,these data suggests that alterations in TEX14 gene has amajor impact on the onset of azoospermia. TEX14 isnow also listed in the OMIM database as being linked to
spermatogenic failure 23 syndrome (OMIM 617707).Furthermore, low TEX14 expression has been reportedin a patient with the SCO syndrome [2].
TEX15 (OMIM 605795) [2, 26, 37, 63, 65, 66]The first nonsense mutation (leading to a prematurestop codon) in the TEX15 locus was identified by exomesequencing in a consanguineous Turkish family [26].The mutation co-segregated with the infertility pheno-type; two brothers with nonobstructive azoospermia andan oligozoospermic sibling were homozygous for themutation. These males presented a drastically reducedtesticular size (by more than 50%) and maturation arrestat the primary spermatocyte stage [26]. Other non-consanguineous siblings with nonobstructive azoosper-mia and a low testicular volume have been found to becompound heterozygotes for deleterious TEX15 variants[25]. To date, few damaging variants have been identi-fied (Table 4). TEX15 has now been linked to spermato-genic failure 25 syndrome in the OMIM database(OMIM 617960). Furthermore, low TEX15 expressionhas been reported in a man with SCO syndrome [2].
Table 6 Variants of TEX genes identified solely in males with azoospermia and/or infertility (Continued)
TEXgene
Study Nucleotide change Protein change Type of mutation Exon/intron
Number of maleswith the alteration
Gershoni et al., 2017 [23] c.2668-2678del early stop codon frameshift deletion Exon 16 2 brothers
TEX15 Cannarella et al., 2020[16]
c.7118G > A p.Ser2373Asn missense mutation Exon 8 1
Araujo et al., 2019 [21] c.7118G > A p.Ser2373Asn missense mutation Exon 8 1 compoundheterozygote
c.9223G > A p.Gly3075Arg missense mutation Exon 10
Wang et al., 2018 [24] c.6934G > A p.R2312X nonsense mutation Exon 1 1
Various studies have assessed the association be-tween TEX15 polymorphisms and male infertility. Onestudy did not find an no association [65]. In 2015,Ruan et al. analyzed the distribution of SNPs of theTEX15 gene within a male Chinese Han population.The researchers reported that two genetic variants(rs323346 and rs323347) in TEX15 gene conferred sus-ceptibility to spermatogenic failure [66]. However, thisfinding was not confirmed by Zhang et al. for rs323346[63].
TEX101 (OMIM 612665)In 2013, TEX101 was first suggested as a biomarker forthe differential diagnosis of azoospermia [57]. Schizaet al. used an ELISA assay to (i) evaluate the seminalplasma level of TEX101 and the success of vasectomy,(ii) stratify forms of azoospermia, and (iii) better selectpatients for sperm retrieval. The same group used differ-ential proteomic profiling to evaluate the impact of thecommon TEX101 missense variant rs35033974 in infer-tile men with various etiologies. They reported that 8cell surface proteins and 9 testis-specific secreted pro-teins were significantly down-regulated in four patientswho were homozygous for rs35033974. The researchers
have also found that the seminal plasma level of TEX101in heterozygous males was five times lower (p = 0.0005)that in controls [57]. Schiza et al. concluded that theTEX101 rs35033974 variant could then be taken into ac-count in diagnosis of infertility.
ConclusionAs expected, TEX genes appear to have a major role inreproduction in general and in spermatogenesis in par-ticular. As the only common feature of TEX genes is theirexpression in the testis, the genes are involved in manydifferent pathways and functions (Fig. 2) in testis cells,germ cells (from spermatogonia to spermatids), Sertolicells, and Leydig cells. This is true not only in humansbut also in all mammals such as the mouse and the rat.In the future, cumulative data on the human TEX genes’physiological functions and pathophysiological dysfunc-tions should become available Furthermore, furtherstudies of the functional effects of natural knockouts orknockdowns in humans are necessary for defining thelist of essential and nonessential testis-specific genes andproteins and thus advancing the biology of humanreproduction.
Fig. 2 Implication of TEX genes during spermatogenesis (Adapted from [67])
Bellil et al. Basic and Clinical Andrology (2021) 31:9 Page 13 of 15
AbbreviationsCAPZA 3: Capping actin protein of muscle Z-line subunit alpha 3; CATSPERZ: CATion channel, SPERm-associated, auxillary subunit Zeta;cDNA: Complementary DNA; cM: Centimorgan; DMC1: DNA MeioticreCombinase 1; DSB: Double-strand breaks; ELISA: Enzyme-linkedImmunosorbent Assay; FANTOM: Functional annotation of the mammaliangenome; HTNS: High in testis but not specific; KO: Knock out; MILI: Miwi-like;MIWI2: (Another PIWI family member); MT: Majority testis; NA: Non available;NP: No predominance; OMIM: Online mendelian inheritance in man; PIWI: P-element induced wimpy testis; RAD51: RAD51 Recombinase; SCO: Sertoli-cell-only; SIX6OS1: Six6 opposite strand transcript 1; SMC3: Structural maintenanceof chromosomes protein 3; SNP: Single nucleotide polymorphisms;SSH: Suppression subtractive hybridization; Sycp2: Synaptonemal complexprotein 2; SYCP1–3: Synaptonemal complex protein 1–3; SYCE1–3: Synaptonemal complex central element protein 1–3; Tctex: T-complextestis-expressed; Tex: Testis expressed; TS: Testis specific; Utp4: U3 smallnucleolar RNA-associated protein 4 homolog; Zfand3: Zinc finger AN1domain-containing protein 3
AcknowledgementsJean-Luc VILOTTE for his comments.
Authors’ contributionsHB, FG, EH: performed the bibliography screening, wrote the paper; BMP:designed the paper and reviewed the paper, FV: designed the paper andwrote the paper. The author (s) read and approved the final manuscript.
FundingNone.
Availability of data and materialsnot applicable.
Ethics approval and consent to participatenot applicable.
Consent for publicationnot applicable.
Competing interestsNone.
Author details1Département de Génétique, CHI de Poissy St Germain en Laye, Poissy,France. 2Université Paris-Saclay, UVSQ, INRAE, BREED, F-78350 Jouy-en-Josas,France. 3Ecole Nationale Vétérinaire d’Alfort, BREED, F-94700 Maisons-Alfort,France.
Received: 2 November 2020 Accepted: 14 February 2021
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